We will define the binding site that the hormone-binding domain of the human androgen receptor uses to attach coactivator proteins. The binding site will be characterized functionally and using single crystal X-ray crystallography. Guided by the three dimensional definition of the coactivator site, we propose to develop potential chemotherapeutic molecules that will inhibit activation of the androgen receptor. The molecules will compete with protein associations required for the receptor to act in controlling transcriptional activation of its target genes. We plan to make these molecules by mimicking the face that the coactivators present to the hormone-binding domain. Our design will be guided by X-ray analysis of receptor structure in its three dimensional complexes with the mimics. Structural studies will be guided by and correlated with biological binding assays. The mimic molecules will be helical and based on peptides. The unnatural molecules are built to confer discrimination and tight binding thereby inhibiting functional activation. Inhibitor molecules will be constructed to permit cellular and nuclear entry and tested in normal and transformed prostate cells to demonstrate inhibition of androgen receptor gene activation. Our experiments will thus provide a distinct pathway for inhibiting androgen receptor sensitive tumor and metastatic cell growth.